Craving can be reliably elicited in the laboratory with humans, is associated with the development of addiction andrelapse, and is a primary target of biological and behavioral interventions. Mesolimbic dopamine neurotransmission has been implicated as the primary neural substrate that underlies the development of craving (i.e., incentive salience) for tobacco and other drugs. Thus, cue-elicited craving represents a potentially powerful endophenotype that is associated with a specific underlying biological mechanism. Our preliminary research has suggested that the DRD4 VNTR polymorphism influences cue-elicited craving for tobacco and alcohol and that this effect is specifically related to dopamine neurotransmission. The proposed research will estimate the heritability of cue-elicited craving, will determine whether the polymorphism influences cue-elicited craving using a within-family design that controls for population effects, will examine how the polymorphism interacts with the environment over a two year period marked by a transition from initial tobacco use to dependence, and test whether an association between the polymorphism and the transition to dependence is mediated by the effect of the polymorphism on the development of cue-elicited craving. Two separate studies are proposed to meet the specific aims of the proposed research. In the first study, MZ and DZ twins who are regular smokers will be exposed to smoking cues in the laboratory after overnight abstinence, and a subset of DZ twins who are discordant for the 7 repeat allele will be compared to their siblings with respect to cue-elicited craving. It is expected that cue-elicited craving will show high heritability and that the discordant DZ twins with the 7 repeat allele will demonstrate significantly more cue-elicited craving as compared to their siblings. In the second study, participants who have recently initiated smoking will be assessed for cue-elicited craving and nicotine dependence at baseline (initial use) and again at one and two years. These data will be used to test whether an association between the polymorphism and the transition to nicotine dependence is mediated by the development of incentive salience for tobacco. The proposed research is expected to lay the foundation for future research on the development of prevention and treatment interventions that specifically target incentive salience for drugs and is expected to guide efforts to match these interventions to the individuals who are most likely to benefit from them.